Table 1.

Maturity-Onset Diabetes of the Young (MODY): Genes and Associated Clinical Features

Gene
(Locus
Name)		% of All
MODY		Clinical FeaturesFrequency of Microvascular ComplicationsReferences /
Selected OMIM Links
ABCC8 1, 2
(MODY12)		<1%Similar to HNF1A- & HNF4A-MODY 3UnknownBowman et al [2012] / 600509
APPL1
(MODY14)		<1% 4Overweight/obesity in someUnknownPrudente et al [2015] / 616511
BLK
(MODY11)		<1% 5Overweight/obesity in someUnknownKim et al [2004], Borowiec et al [2009] / 613375
CEL
(MODY8)		<1% 6
  • Pancreatic atrophy → exocrine pancreatic insufficiency
  • Fibrosis & lipomatosis → diabetes
UnknownRaeder et al [2006], Johansson et al [2011] / 609812
GCK
(MODY2)		30%-50% 7, 8
  • Stable, mild fasting hyperglycemia at birth
  • Typically asymptomatic; diagnosis often incidental
Rare 9Froguel et al [1993], Pearson et al [2001] / 125851
HNF1A 3
(MODY3)		30%-65% 7, 10, 11
  • Transient neonatal hyperinsulinemic hypoglycemia in some
  • Progressive insulin secretory defect
  • OGTT frequently needed to make an early diagnosis
  • Renal glycosuria
Common 12Stride et al [2005] / 600496
HNF1B
(MODY5)		<5% 13
  • IUGR
  • Renal anomalies
  • Urogenital tract anomalies
  • Pancreatic hypoplasia
Common 12Montoli et al [2002], Bellanné-Chantelot et al [2004], Ulinski et al [2006], Faguer et al [2011] / 137920
HNF4A 2
(MODY1)		5%-10% 14
  • Birth weight >800 g above normal
  • Transient neonatal hyperinsulinemic hypoglycemia common 15
  • Progressive insulin secretory defect
Common 12Fajans et al [2001], Pearson et al [2005], Pearson et al [2007], Shields et al [2010] / 125850
INS 1
(MODY10)		<1%UnknownEdghill et al [2008a], Meur et al [2010] / 613370
KCNJ11 1, 2
(MODY13)		<1%Similar to HNF1A-MODY & HNF4A-MODY 3UnknownBonnefond et al [2012], Liu et al [2013] / 616329
KLF11
(MODY7)		<1% 5UnknownNeve et al [2005], Fernandez-Zapico et al [2009] / 610508
NEUROD1
(MODY6)		<1% 5Overweight/obesity in someUnknownMalecki et al [1999], Kristinsson et al [2001] / 606394
PAX4
(MODY9)		<1% 5UnknownMauvais-Jarvis et al [2004], Plengvidhya et al [2007] / 612225
PDX1 1
(MODY4)		1% 5Overweight/obesity in someUnknownWright et al [1993], Stoffers et al [1997], Fajans et al [2010] / 606392

IUGR = intrauterine growth restriction; OGTT = oral glucose tolerance test

1.

Pathogenic variants in this gene are also associated with permanent neonatal diabetes mellitus.

2.

Pathogenic variants in this gene are also associated with familial hyperinsulinism.

3.

Should be considered in patients responsive to sulfonylurea who test negative for HNF1A-MODY and HNF4A-MODY

4.

Two APPL1 loss-of-function variants reported

5.

Some variants in BLK, KLF11, NEUROD1, PAX4, and PDX1 reported in the Human Gene Mutation Database (HGMD) as pathogenic are present in the Genome Aggregation Database (gnomAD) at population frequencies that are not consistent with their potential clinical significance. Additional studies are necessary to better understand the association of variants in these genes with MODY.

6.

One individual had a large CEL deletion (429 nucleotides) [Ellard et al 2013].

7.

Depending on the population studied

8.

~1.8% of GCK-MODY is associated with whole-gene or exon deletions [Garin et al 2008].

9.
10.
11.

~1.2% of HNF1A-MODY is associated with whole-gene or exon deletions [Colclough et al 2013].

12.

Related to overall glycemic control [Bacon et al 2016a, Bacon et al 2016b]

13.

~33% of HNF1B-MODY is associated with whole-gene or exon deletions [Bellanné-Chantelot et al 2005].

14.

~1.9% of HNF4A-MODY is associated with whole-gene or exon deletions [Colclough et al 2013].

15.

Individuals with HNF4A-MODY may also have reduced levels of lipoprotein A1, lipoprotein A2, and HDL cholesterol and increased levels of LDL-cholesterol, similar to the lipid profiles seen in type 2 diabetes mellitus [Pearson et al 2005].

From: Maturity-Onset Diabetes of the Young Overview

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